In the past funding period, we focused on the production of new, immature B-cells in aged mice by assessing kinetics of production, number of cells produced/day, and population turnover in the bone marrow and spleen. We found that B-lineage precursors decline with age, but newly-made B cells are generated in the bone marrow of aged animals at about the same rate as that observed in young animals. In spite of ongoing formation of new B-cells in the aged, few of these newly-made B-cells become part of the transitional or mature B-cell pools in the spleens. Kinetic studies indicate that splenic B-cells turn over very slowly and are long-lived in aged mice. We and others have concluded that B-cell homeostasis differs in aged mice from the well described homeostatic patterns of young mice. Furthermore, our results imply that a major defect is the inability of immature B-cells to join the peripheral B cell compartments. Adoptive transfer studies show that even young immature B-cells cannot home effectively to an aged spleen, suggesting a deficiency in the aged tissue microenvironment. In contrast, immature B-cells from aged mice are equally able to home to spleen compared to those from young mice. The tissue architecture of aged spleen and lymph nodes is disrupted in appearance and chemokine production is reduced, which likely alters lymphocyte migration and homeostasis. Thus, our results emphasize the acute need to know more about how immune homeostasis changes with age. Two general premises are addressed in this renewal application: (1) We hypothesize that B-cell homeostasis changes because the marrow and splenic microenvironments are altered during aging. (2) We propose that alterations in the microenvironments are modulated by changes in the types of B-cells populating the marrow and secondary tissues. Aim I will define the deficiencies of the aged lymphoid microenvironment that affect B-cell homeostasis and the homing and retention of newly-made B-cells. Aim II addresses the hypothesis that the long-lived, mature B-cells found in the spleens of aged mice are insufficient to maintain chemokine production and normal lymphoid compartmentalization. Aim III proposes that mature and effector B-cell populations (plasma cells), which are retained in bone marrow in increasing numbers with age, actually alter the ability of marrow stromal cells to function in B-lymphopoiesis. We believe that changes in B-cell homeostasis may predict poor immune function in the aged.